As synthetic small molecules continue to interface with an increasingly large swath of biology (Stockwell (2004) NATURE 432: 846; Schreiber (1996) BIOORG. MED. CHEM. 6: 1127), researchers have sought new approaches to rapidly create highly diverse collections of small molecules (Burke et al. (2004) ANGEW. CHEM., INT. ED. 43: 46). Early small-molecule libraries generally contained a single core scaffold decorated by different chemical groups (Bunin et al. (1994) PROC. NATL. ACAD. SCI. U.S.A. 91: 4708). Later efforts introduced modest structural variation in the central scaffold (Ding et al. (2002) J. AM. CHEM. SOC. 124: 1594).
The vast majority of current library synthesis efforts are based on solid-phase, split-pool methodologies (Furka et al. (1991) INT. J. PEPT. PROTEIN RES. 37: 487; Merrifield (1963) J. AM. CHEM. SOC. 85: 2149). While these methods offer technical advantages, they also limit the diversity of structures that can be created. Notably, it is generally not possible to direct a specific fraction of beads (for example, those beads containing molecules with a primary amine group) to one of several possible subsequent reaction conditions (for example, exposure to an acylating agent). As a result, every intermediate in a split-pool library synthesis must be reactive toward any reactant it may encounter in a subsequent step. Moreover, it usually is not possible to purify unreacted support-bound starting material away from desired products after each library synthesis step, so only highly efficient reactions can be used. These limitations constrain the amount of diversity that can be borne in early steps of a library synthesis. As a result, the diversification of scaffolds during library synthesis has thus far been limited to a single (predominantly terminal) step (Burke et al. (2003), SCIENCE 302, 613; Burke et al. (2004) J. AM. CHEM. SOC. 126: 14095; Oguri et al. (2005) ORG. LETT. 7: 47; Taylor et al. (2004) ANGEW. CHEM., INT. ED. 43: 1681).
Thus, there remains a need for efficient and effective methodologies that permit iterative branching reaction pathways to occur in a single reaction mixture at each step in a synthetic scheme for producing a library of compounds.